3. Ethics Committee (EC)/Institutional Review Board (IRB)

3.1 Provide a list of documents needed to be submitted for EC/IRB review and approval including the number of copies and/or translations as relevant.

The FDA has published a list of FAQs: Institutional Review Boards Frequently Asked Questions Guidance for Institutional Review Boards and Clinical Investigators. 

Each IRB is different and, as a consequence, the documents required by each to be submitted may differ. The FDA has published “Institutional Review Board (IRB) Written Procedures: Guidance for Institutions and IRBs. The standard documentation required is likely to be as follows; however, consult the applicable IRB. 

1. Protocol and any amendments
2. CRF (if applicable)
3. Informed consent form(s)
4. Translation of the informed consent form for non-English speaking subjects, when applicable
5. Any other written information to be provided to the subject(s)
6. Advertisement for subject recruitment (if used)
7. Subject compensation (if any)

This is consistent with the FDA’s “E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) - Guidance for Industry”.

3.2 Time required for EC/IRB review and approval process and turnaround time if any query is raised during the review process.

It will depend on the type of IRB used.

Central IRBs tend to meet very frequently, and review timelines can be quite fast; however, local IRB timelines may be longer.

3.3 Does EC/IRB have any fast-track or expedited review process?

Yes, in certain circumstances.

45CFR46.110 provides for an expedited review process by an IRB in certain circumstances, “for certain kinds of research involving no more than minimal risk, and for minor changes in approved research.” The adoption of an expedited process by an IRB is not obligatory.

As 21CFR46.110 sets out:

“An IRB may use the expedited review procedure to review either or both of the following: 

1. Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk,
2. minor changes in previously approved research during the period (of 1 year or less) for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the IRB chairperson from among the members of the IRB. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove of the research. A research activity may be disapproved only after review in accordance with the non-expedited review procedure....”.

3.4 Does EC/IRB need to be registered and/or accredited/approved by RA/CA?

Each IRB must register with the U.S. Office for Human Research Protections (OHRP).

21CFR56.106 - Registration provides that: “Each IRB in the United States that reviews clinical investigations regulated by FDA…. and each IRB in the United States that reviews clinical investigations that are intended to support applications for research or marketing permits for FDA-regulated products must register at a site maintained by the Department of Health and Human Services (HHS). (A research permit…. is usually known as an investigational new drug application (IND)…. [or] an investigational device exemption (IDE)). An individual authorized to act on the IRB's behalf must submit the registration information. All other IRBs may register voluntarily.”

The registration is neither certification nor accreditation that the individual IRB is in full compliance with 21CFR56  – see the FDA’s guidance – Frequently Asked Questions- IRB Registration (July 2009).

3.5 How frequently do EC/IRB meet?

The frequency of IRB meetings is not stipulated. So far as we were able to determine, it is likely to vary by, and be specific to, individual IRBs.

3.6 Is any additional approval required apart from the EC/IRB (e.g. scientific committee, subject matter expert committee, etc.)?

Yes, in certain circumstances.

21CFR56.112 - Review by Institution provides that “Research covered by these regulations that has been approved by an IRB may be subject to further appropriate review and approval or disapproval by officials of the institution. However, those officials may not approve the research if it has not been approved by an IRB.” 

3.7 Please describe the process of the EC/IRB submission for clinical trial approval.

The process of IRB submission is dependent on the individual IRB. 21CFR56.108 - IRB Functions and Operations does however provide that: 

“[i]n order to fulfil the requirements…. each IRB shall:

a. Follow written procedures:

1. for conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution;
2. for determining which projects require review more often than annually and which projects need verification from sources other than the investigator that no material changes have occurred since the previous IRB review; 
3. for ensuring prompt reporting to the IRB of changes in research activity; and 
4. for ensuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects. 

b. Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of:

1. any unanticipated problems involving risks to human subjects or others; 
2. any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; or 
3. any suspension or termination of IRB approval. 

c. Except when an expedited review procedure is used…. review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in non-scientific areas. In order for the research to be approved, it shall receive the approval of a majority of those members present at the meeting.”

3.8 What is the relevant EC/IRB fee in local currency/USD? (e.g., is the fee different for notification/approval, initial submission, amendment, study with IMPD and study without IMPD, investigator site addition, etc.)?

Many IRBs charge fees to review research proposals and these are unregulated by either the Department of Health & Human Services or the FDA. The fee charges are likely to vary and be specific to individual IRBs.

3.9 Does EC/IRB accept checks or can payment be made electronically? Please provide details on (1) A/C number; (2) A/C Name; (3) Sort Code; (4) Swift Code; (5) Bank address, etc. Where can remittance advice notices be sent?

No specific guidance was found in this regard since it is likely to vary by, and be specific to, individual IRBs.

3.10 Is there any guidance tool available for making electronic applications? If yes, provide the link and/or step-by-step instructions.

No specific guidance was found in this regard since it is likely to vary by, and be specific to, individual IRBs.

Central IRBs such as Advarra or WCG IRB have online platforms where submission documents are uploaded.

3.11 Does EC/IRB require any mock screens/screenshots of participant-facing material on the app? If yes, do these need to be submitted in the local language?

Normally, IRBs would request screenshots of digital information such eConsent. However, it is best to consult with the applicable IRB.

The FDA Guidance “Use of Electronic Informed Consent in Clinical Investigations – Questions and Answers Guidance for Institutional Review Boards, Investigators, and Sponsors” (December 2016) indicates what are the materials that a participant should see as part of the eIC process, that the sponsor should submit to the IRB:

“Q12. What eIC materials should the investigator submit to the IRB? 

The investigator should submit to the IRB copies of all forms (electronic and paper forms) and informational materials, including any videos and Web-based presentations, which the subject will receive and view during the eIC process. The investigator must obtain IRB approval for any subsequent modifications to the study-related information, whether electronic or in hard copy (see 45 CFR 46.109 and 21 CFR 56.109). OHRP and FDA recommend that an investigator discuss plans for using eIC with the IRB before finalizing development of the eIC to ensure that the IRB agrees that such a format may be used for the applicable research for obtaining informed consent.” 

3.12 Does the EC/IRB have any template or specific element requirements on ICF and/or other participant-facing materials?

Yes.

IRBs tend to have their own templates for ICFs, Assents, and other supportive documents such as the California Bill of Rights, etc.

The FDA’s Guidance “Informed Consent: Guidance for IRBs, Clinical Investigator, and Sponsors (Aug 2023) provides detailed regulatory requirements for informed consent and a discussion of the roles of IRBs, clinical investigators, sponsors, and FDA related to informed consent. The FDA issued a final rule which went into effect on 22^nd January 2024. This final rule allows an exception from the requirement to obtain informed consent when a clinical investigation poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of human subjects. The final rule permits an institutional review board (IRB) to waive or alter certain informed consent elements or to waive the requirement to obtain informed consent, under limited conditions, for certain FDA-regulated minimal-risk clinical investigations.

Based on 21CFR50.25, the Final Rule, and the US-ICH-GCPR2, the informed consent form must include the following information, as applicable:

• The study purpose, procedures, and expected duration of the trial
• Identification of any experimental procedures
• Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
• Any expected benefits to the participant
• Disclosure of appropriate alternative procedures that might be advantageous to the participant
• Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Contact information for relevant individuals to contact in the event of a trial-related injury
• That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
• Foreseeable circumstances under which the investigator may remove the participant without consent
• Any expenses the participant needs to pay to participate in the trial
• The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
• Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
• Approximate number of participants in the study

As per 21CFR50, for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

Other elements to be included in the ICF are: 

• Whether research results will be disclosed to participants.
• Whether or not the participant’s information or biospecimens will be used or distributed for future research.
• That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit.
• Whether biospecimens research may include whole genome sequencing.
• If in the event of injury, compensation is not available, the consent should include a statement informing the participant.

3.13 Is there any guidance tool on participant compensation including clinical study-related injury per local requirements?

Yes, there is guidance available – In January 2018, the FDA released an Information Sheet “Payment and Reimbursement to Research Subjects Guidance for Institutional Review Boards and Clinical Investigators”.

This guidance indicates that “the IRB should determine that the risks to subjects are reasonable in relation to anticipated benefits {21 CFR 56.111 (a)(2)] …”

“Paying research subjects in exchange for their participation is a common and, in general, acceptable practice. Payment to research subjects for participation in studies is not considered a benefit that would be part of the weighing of benefits or risks; it is a recruitment incentive. FDA recognizes that payment for participation may raise difficult questions that should be addressed by the IRB. For example, how much money should research subjects receive, and for what should subjects receive payment, such as their time, inconvenience, discomfort, or some other consideration? 

In contrast to payment for participation, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence. Other than reimbursement for reasonable travel and lodging expenses, IRBs should be sensitive to whether other aspects of proposed payment for participation could present an undue influence, thus interfering with the potential subjects’ ability to give voluntary informed consent. 

Payment for participation in research should be just and fair. The amount and schedule of all payments should be presented to the IRB at the time of initial review. The IRB should review both the amount of payment and the proposed method and timing of disbursement to assure that neither are coercive or present undue influence.”

FDA’s Guidance on Informed Consent provides clarification on “Compensation and Medical Treatment in Event of Injury”:

“6. Compensation and Medical Treatment in Event of Injury:

For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. (21 CFR 50.25(a)(6))

For clinical investigations involving more than minimal risk, the informed consent process must describe any compensation and medical treatments available to subjects if injury occurs33 (21 CFR 50.25(a)(6)). Because available compensation and medical treatments may vary depending on the medical circumstances of the individual subject or the policies of the institution, the consent process should include an explanation to subjects of where they may obtain further information. An example of an adequate statement is: 

“The sponsor has made plans to pay for medical costs related to research-related injuries” 

followed by an explanation of how to obtain further information. If no compensation is available, the consent process should include a statement such as:

“Because of hospital policy, the hospital is not able to pay for your medical care if you are injured as a result of being in this study. If you are injured as a result of being in this study, you or your insurance will be responsible for paying your medical expenses. However, you do not give up any of your legal rights by being in this study, and you may choose to pursue legal action if you are injured by being in the study.”

3.14 Are there any specific local safety reporting requirements for clinical studies?

Yes - see the FDA’s Guidance Document “Adverse Event Reporting to IRBs — Improving Human Subject Protection”. Guidance for Clinical Investigators, Sponsors, and IRBs (January 2009).

The introduction to this guidance includes the statement that “[s]pecifically, the guidance provides recommendations for sponsors and investigators conducting investigational new drug (IND) trials to help them differentiate between those adverse events that are unanticipated problems that must be reported to an IRB and those that are not. The guidance also makes suggestions about how to make communicating adverse events information to IRBs more efficient."

“FDA developed this guidance in response to concerns raised by the IRB community, including concerns raised at a March 2005 public hearing, that increasingly large volumes of individual adverse event reports submitted to IRBs—often lacking in context and detail—are inhibiting, rather than enhancing, the ability of IRBs to protect human subjects.”

The guidance sets out the reporting obligations for AEs: for clinical investigations of drug and biological products conducted under an investigational new drug (IND) application, information about adverse events must be communicated among investigators, sponsors, and IRBs as follows:

• Investigators are required to report promptly “to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by the drug. If the adverse effect is alarming, the investigator shall report the adverse effect immediately” (21CFR312.64 (b)).
• Sponsors are specifically required to notify all participating investigators (and FDA) in a written IND safety report of “any adverse experience associated with the use of the drug that is both serious and unexpected” and “any finding from tests in laboratory animals that suggests a significant risk for human subjects” (21CFR312.32). More generally, sponsors are required to “keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use” (21CFR312.55).

The FDA explains what are “unexpected problems”, which are reportable. Therefore, the FDA recommends that there be careful consideration of whether an AE is an unanticipated problem that must be reported to IRBs. In summary, FDA believes that only the following AEs should be considered as unanticipated problems that must be reported to the IRB:

• A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug exposure (such as angioedema, agranulocytosis, hepatic injury, or Stevens-Johnson syndrome).
•  A single occurrence, or more often a small number of occurrences, of a serious, unexpected event that is not commonly associated with drug exposure, but uncommon in the study population (e.g., tendon rupture, progressive multifocal leukoencephalopathy).
•  Multiple occurrences of an AE that, based on an aggregate analysis, is determined to be an unanticipated problem. There should be a determination that the series of AEs represents a signal that the AEs were not just isolated occurrences and involve risk to human subjects (e.g., a comparison of rates across treatment groups reveals a higher rate in the drug treatment arm versus a control). We recommend that a summary and analyses supporting the determination accompany the report.
•  An AE that is described or addressed in the investigator’s brochure, protocol, or informed consent documents, but occurs at a specificity or severity that is inconsistent with prior observations. For example, if transaminase elevation is listed in the investigator’s brochure and hepatic necrosis is observed in study subjects, hepatic necrosis would be considered an unanticipated problem involving risk to human subjects. We recommend that a discussion of the divergence from the expected specificity or severity accompany the report.
•  A serious AE that is described or addressed in the investigator’s brochure, protocol, or informed consent documents, but for which the rate of occurrence in the study represents a clinically significant increase in the expected rate of occurrence (ordinarily, reporting would only be triggered if there were a credible baseline rate for comparison). We recommend that a discussion of the divergence from the expected rate accompany the report.
•  Any other AE or safety finding (e.g., based on animal or epidemiologic data) that would cause the sponsor to modify the investigator’s brochure, study protocol, or informed consent documents, or would prompt other action by the IRB to ensure the protection of human subjects. We recommend that an explanation of the conclusion accompany the report.

An unexpected adverse drug experience is defined by the FDA as “[a]ny adverse drug experience, the specificity or severity of which is not consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. Unexpected, as used in this definition, refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator brochure), rather than from the perspective of such experience not being anticipated from the pharmacological properties of the pharmaceutical product.” (21CFR312.32).

3.15 Does the EC/IRB require any periodic study reporting?

Yes, periodic re-review (also known as “Continuing Review”) is required not less than once/year: “[a]n IRB shall conduct continuing review of research covered by these regulations at intervals appropriate to the degree of risk, but not less than once per year, and shall have authority to observe or have a third party observe the consent process and the research.” (21CFR56.109). 

Additionally, the FDA published guidance on E2F Development Safety Update Report in 2011 encouraging sponsors to prepare DSURs annually, for submission to regulatory authorities.